Patent EP-2228375-A1 (EP)
Inventor: HIMMELSBACH FRANK
IPC: A61K31/522
Filed: 2003-11-03
Abstract: 1-(Benzoheterocyclyl-alkyl)-7-alkyl-8-(N-containing heterocyclyl, amino-cycloalkyl or aminoalkyl)-xanthine derivatives (I) are new. Xanthine derivatives of formula (I) and their tautomers, enantiomers, diastereomers (or mixtures), prodrugs and salts are new. [Image] R 1>-T-R a; T : 1-3C alkyl; R ae.g. 5-oxo-4,5-dihydro-benzo-(f)(1,3,4)-oxadiazepinyl; 11H-dibenz-(b,e)-azepinyl or 5H-dibenzo-(a,d)-cycloheptenyl (both optionally having a CH in the heterocycle replaced by S, O, CO, SO, SO 2 or NR x); or phenanthridinyl, 1,2,3,4-tetrahydro-phenanthridinyl, 5H-dibenzo-(d,f)(1,3)-diazepinyl, 5H-benzo-(e)-pyrrolo-(1,2-a)(1,4)-diazepinyl, thieno-(3,2-b)(1,4)-benzoxazepinyl or 3-oxo-2,3-dihydro-isoindol-1-ylene; where all R a groups are substituted by R 1> 0> - R 1> 3> (and optionally also by T) and optionally have 1-3 CH in the benzo ring replaced by N; R xH, alkyl, 2-4C alkenyl, 2-4C alkynyl, cycloalkyl, -T-cycloalkyl, Ar or -T-Ar; 2-4C alkyl substituted by OH, OT, cycloalkoxy, NH 2, NHT or NT 2; COT, COOT, -T-COOT, COAr, SO 2T or SO 2Ar; R 1> 0>e.g. H, halo, alkyl, Ar-SO 2NH-, Ar-T-SO 2NH-, -NT-COT, -NT-COAr, -NT-CO-T-Ar, -NT-COOT, N(T)CONH 2, N(T)CONHT, N(T)CONT 2, NTSO 2T, NTSO 2Ar or NTSO 2-T-Ar; 2-oxo-imidazolidino; R 1> 1>, R 1> 2>H, halo, T, CF 3, OH, OT or CN; or R 1> 1> + R 1> 2>OCH 2O, OCF 2O or 3-5C n-alkylene (bonded to adjacent C); R 1> 3>H, F, Cl, Br, T, CF 3 or OT; R 2>e.g. H, cycloalkyl, -T-cycloalkyl, tetrahydrofuran-3-yl, tetrahydropyran-(3 or 4)-yl, tetrahydrofuranylmethyl, tetrahydropyranylmethyl, Ar, Ar-alkyl, Ar-(2-3C) alkenyl, ArCO-(1-2C) alkyl, Het-T-, furanyl-COCH 2-, thienyl-COCH 2-, thiazolyl-COCH 2-, pyridyl-COCH 2-, alkylcarbonyl-(1-2C) alkyl, Ar-A-T- or R b-substituted alkyl; A : O, S, NH, NT, SO or SO 2; R bCN, COOH, COOT, CONH 2, CONHT, CONT 2, -CO-pyrrolidino, -CO-piperidino, -CO-morpholino, -CO-piperazino, CO-(N-(methyl or ethyl)-piperazino) or 2-4C alkyl substituted (but not in the 1-position) by R c; R cOH, OT, NH 2, NHT, NT 2, pyrrolidino, piperidino, -morpholino, piperazino or N-(methyl or ethyl)-piperazino; R 3>3-8C alkyl or -T-R d; R 4>azetidino or pyrrolidino, substituted in the 3-position by R 1> 9> and os by 1 or 2 T; piperidino or homopiperidino, substituted in the 3- or 4-position by R 1> 9> and os by 1 or 2 T; 3-amino-piperidino, ring-substituted by CONH 2, mono- or di-(1-2C alkyl)-carbamyl, pyrrolidino-CO-, 2-cyano-pyrrolidino-CO-, thiazolidino-CO-, 4-cyano-thiazolidino-CO-, piperidino-CO- or morpholino-CO-; 3-amino-(4 or 5)-(hydroxy or methoxy)-piperidino; 3-amino-(2 or 6)-oxo-piperidino; piperidino or homopiperidino, substituted in the 3-position by R 1> 9> and carrying an alkylene bridge of 2-5C if bonded to the same C, 1-4C if bonded to adjacent C's or C's separated by one atom or 1-3C if bonded to C's separated by 2 atoms; azetidino, pyrrolidino, piperidino or homopiperidino substituted by -T-R 1> 9>; piperazino, homopiperazino, 3-imino-piperazino, 3-imino-homopiperazino or 5-imino-homopiperazino (all os on C by 1 or 2 T); 6-amino-homopiperazino (os by 1 or 2 T); Cyc, Cyc-(1-2C) alkyl, Cyc-NH-, Cyc-NT-, Cyc-(1-2C) alkyl-NH- or Cyc-(1-2C) alkyl-NT-; R 1> 9>-(2-4C) alkyl-NH- or R 1> 9>-(2-4C) alkyl-NT- (in which R 1> 9> is separated from the amino N by at least 2C); NHR 2> 0>, N(T)R 2> 0>, R 1> 9>-(3-4C)-n-alkyl (os in the alkyl by 1 or 2 T), 3-amino-2-oxo-piperidin-5-yl or 3-amino-2-oxo-1-methyl-piperidin-5-yl; pyrrolidin-3-yl, piperidin-(3 or 4)-yl or homopiperidin-(3 or 4)-yl, all substituted in the 1-position by R 1> 9>; or azetidin-(2 or 3)-yl(m)ethyl, pyrrolidin-3-yl, pyrrolidin-(2 or 3)-yl(m)ethyl, piperidin-(3 or 4)-yl or piperidin-(2, 3 or 4)-yl(m)ethyl (all os by 1 or 2 T); R d3-7C cycloalkyl or 3-7C cycloalkenyl (both os by 1 or 2 T); aryl; furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidyl or pyrazinyl (all os by one or 2 T or by halo, CF 3 CN, or OT); 3-8C alkenyl, 3-6C alkenyl (os by F, Cl, Br or CF 3), alkynyl, aryl or aryl-2-4C alkenyl; Cyc : 3-7C cycloalkyl ring-substituted by R 1> 9> or -T-R 1> 9>; provided that in Cyc-NH- or Cyc-NT- substituted by R 1> 9> the N-atoms are separated by at least 2C; R 1> 9>NH 2, NHT or NT 2; R 2> 0>azetidin-3-yl, azetidin-(2 or 3)-ylmethyl, pyrrolidin-3-yl, pyrrolidin-(2 or 3)-ylmethyl, piperidin-(3 or 4)-yl or piperidin-(2, 3 or 4)-ylmethyl (all os by 1 or 2 T); Ar : phenyl or naphthyl, both os by 1 or 2 R h; R hhalo, CF 3, CN, NO 2, NH 2, CONH 2, SO 2NH 2, SO 2Me, NHCOMe, NHSO 2Me, T, cyclopropyl, CH=CH 2, CCH, OH, OT, OCHF 2 or OCF 3; Het : pyrrolyl, furanyl, thienyl or pyridyl (all optionally having 1 or 2 CH replaced by N); or indolyl, benzothienyl, benzofuranyl, quinolinyl or isoquinolinyl (all optionally having 1-3 CH replaced by N); (all Het groups being os by 1 or 2 R h); Alkyl moieties have 1-4C and cycloalkyl moieties 3-6C unless specified otherwise. Full definitions are given in the Definitions Field (Full Definitions). An independent claim is included for the preparation of (I). ACTIVITY : Antidiabetic; antiarthritic; anorectic; immunosuppressive; osteopathic; antilipemic; antiarteriosclerotic; tranquilizer; cardiant; diuretic; hypotensive; nephrotropic; antiinflammatory; antiinfertility. MECHANISM OF ACTION : Dipeptidylpeptidase-IV (DPP-IV) inhibitor; B-cell degeneration inhibitor; glucagon-like peptide (GLP) action modulator. 1-((Phenanthridin-6-yl)-methyl)-3-methyl-7-(2-butyn-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine dihydrochloride (Ia) had IC 5 0 5 nM for inhibition of DPP-IV.